Biocompatible Polyacrylate Compositions For Medical Applications

ABSTRACT

A composition comprising a structural component comprising linear acrylic homopolymers or linear acrylic copolymers and a biobeneficial component comprising copolymers having an acrylate moiety and a biobeneficial moiety is disclosed. A medical article comprising the composition in the coating thereof and a method of fabricating the medical article are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/819,128 filed on Jun. 18, 2010, which is a divisional applicationof U.S. application Ser. No. 10/815,421 filed on Mar. 31, 2004, now U.S.Pat. No. 7,758,880 issued on Jul. 20, 2010, which is acontinuation-in-part of U.S. application Ser. No. 10/317,435 filed onDec. 11, 2002, now U.S. Pat. No. 7,776,926 issued on Aug. 17, 2010, theteachings of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

This invention is directed to polymers used in medical applications,such as coatings for medical devices or implantable prostheses.

DESCRIPTION OF THE STATE OF THE ART

Among the many advances in medical practice in recent years is thedevelopment of medical devices that supplement the surgeon's skills.Examples of these are a variety of vascular catheters and guide wiresthat can be used to treat remote areas of the circulatory systemotherwise available only by major surgery. Another is a stent, a devicethat retards restenosis after angioplasty. Another is the intra-ocularlens that restores youthful eyesight to the elderly afflicted withcataracts. Heart valves, artificial pacemakers, and orthopedic implantsare among a lengthening list.

Nearly all of the above-described devices are constructed of plasticsand metals that were never intended to invade, and sometimes reside forprolonged periods, in the human body. These devices present surfacesthat bear little or no semblance to those of the human organs, which aregenerally hydrophilic, slippery, and obviously biocompatible. Thepenalty imposed on invasive devices that are not biocompatible is thatthey tend to be treated as foreign objects by the body's immune system.Inflammation and thrombosis often result.

The surface of devices already designed and manufactured from suchmaterials can be made biocompatible, as well as hydrophilic andslippery, by properly designed coatings. Thus, the way has been openedto construct medical devices from conventional plastics and metalshaving the particular physical properties required, and then to applysuitable coatings to impart the desired properties to their surfaces.

In addition to improving the biocompatibility of the surface, polymerscan be used to deliver biologically or pharmaceutically active agents toa treatment site. For example, stents have been modified with polymersfor local application of a therapeutic substance. In order to provide aneffective concentration at the treatment site, systemic administrationof medication often produces adverse or toxic side effects for thepatient. Local delivery is a preferred method of treatment, becausesmaller total levels of medication are administered in comparison tosystemic dosages, and this medication is concentrated at a specificsite. Local delivery thus produces fewer side effects and achievesbetter results. Briefly, a solution that includes a solvent, a polymerdissolved in the solvent, and a therapeutic substance dispersed in theblend is applied to the stent. The solvent is then allowed to evaporate,leaving on the stent surface a coating of the polymer and thetherapeutic substance impregnated in the polymer. Once the stent hasbeen implanted at the treatment site, the therapeutic substance isreleased from the polymer coating over time.

Although using coated stents improves pharmacological treatment of thepatient and improves biocompatibility of the medical device in thepatient, coatings can still be improved. In particular, it is desirableto have biologically beneficial (biobeneficial) stent coatings that arecreep compliant and are capable of providing modulated drug release rateby increased water absorption in the overall coating. The embodiments ofthe present invention provide stent coatings that have these and otheradvantages.

SUMMARY

A composition is provided including a biologically compatible structuralcomponent such as a linear acrylic homopolymers, linear acryliccopolymers, or styrene and a biobeneficial component comprisingcopolymers having a bioactive or biobeneficial moiety. The biobeneficialcomponent can also comprise an acrylate moiety. The composition can beused as a coating in medical applications such as for a stent. Thecomposition can also be used for delivery of a drug or therapeuticsubstance. The mass ratio between the structural component and thebiobeneficial component can be between about 99:1 and about 1:1, morenarrowly, between about 19:1 and about 9:1, such as about 3:1. Examplesof acrylic homopolymers and linear acrylic copolymers that can be usedfor making the structural component include poly(methylmethacrylate),poly(ethylmethacrylate), poly(n-propyl methacrylate),poly(isopropylmethacrylate), poly(n-butylmethacrylate),poly(n-laurylmethacrylate), poly(2-hydroxyethylmethacrylate),poly(methylmethacrylate-co-2-hydroxyethyl methacrylate),poly(n-butylmethacrylate-co-2-hydroxyethyl methacrylate), and mixturesthereof. One example of a copolymer comprising the biobeneficialcomponent can be a block copolymer having the formula

wherein m₁, n₁, p₁, r₁, m₂, n₂, p₂, and r₂ are all integers, whereineach of m₁, m₂, p₁, and p₂ can be 0 or greater; each of n₁, n₂, r₁, andr₂ can be greater than 0, and r₁ and r₂ can be the same or different; m₁and m₂ can be the same or different; n₁ and n₂ can be the same ordifferent; and p₁ and p₂ can be the same or different; X can be hydrogenor methyl group; each of R and R₁, independently, can be methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, lauryl,or 2-hydroxyethyl; and Q can be a fragment that provides thebiobeneficial properties. Q fragments can be derived from poly(alkyleneglycols), superoxide dismutate-mimetics (SODm), diazenium diolate-typenitric oxide donors, polycationic peptides, polysaccharides,pyrrolidone, vitamin E, sulfonated dextrane, β-phenoxyethanol,N,N-dimethylamino-2-ethanol, mannose-6-phosphate, sulfonic acid andderivatives of sulfonic acid, among others.

This invention also relates to a medical article fabrication method. Themethod comprises preparing a polymeric combination comprising astructural component including linear acrylic homopolymers or linearacrylic copolymers and a biobeneficial component comprising copolymershaving an acrylate moiety and a biobeneficial moiety and forming amedical article from the combination or depositing the combination on amedical article. The biobeneficial component can include random, block,graft, or brush copolymers. One method of making block copolymersincludes copolymerizing an acrylate and a biobeneficial monomer using ofliving, free-radical copolymerization with initiation-transfer-agenttermination of the living chains.

DETAILED DESCRIPTION Terms and Definitions

The following definitions apply:

The terms “block copolymer” and “graft copolymer” follow the terminologyused by the International Union of Pure and Applied Chemistry (IUPAC).“Block copolymer” refers to a copolymer containing a linear arrangementof blocks. A block is defined as a portion of a polymer molecule inwhich the monomeric units have at least one constitutional orconfigurational feature absent from adjacent portions. “Graft copolymer”refers to a polymer composed of macromolecules with one or more speciesof blocks connected to the main chain as side chains, havingconstitutional or configurational features different than those in themain chain.

The term “AB-block copolymer” is defined as a block copolymer havingmoieties A and B arranged according to the general formula-{[A-]m-[B]n}x-, where each of m, n, and x is a positive integer, and mcan be ≧2, and n can be ≧2.

The term “ABA-block copolymer” is defined as a block copolymer havingmoieties A and B arranged according to the general formula-{[A-]m-[B-]n-[A]p}x-, where each of m, n, p, and x is a positiveinteger, and m can be ≧2, and n can be ≧2, and p can be ≧2.

The term “ABC-block copolymer” is defined as a block copolymer havingmoieties A, B, and C arranged according to the general formula-{[A-]m-[B-]n-[C]p}x- where each of m, n, p, and x is a positiveinteger, and m can be ≧2, and n can be ≧2, and p can ≧2.

These blocks need not be linked at the ends, since the values of theintegers determining block length ensure that the individual blocks arepolymers in their own right. Accordingly, the ABA-block copolymer can benamed poly A-block-co-poly B-block-co-poly A-block copolymer, theABC-block copolymer can be named poly A-block-co-poly B-block-co-polyC-block copolymer and the AB-block co-polymer can be named polyA-block-co-poly B-block copolymer. Blocks A, B, and C can be longer thanthree blocks and can be alternating or random.

Note that the term “copolymer” encompasses for purposes of thisdisclosure a polymer with two or more constituent monomers and does notimply a polymer of only two monomers.

The term “brush copolymer” includes two copolymer types. The first typeincludes copolymers with some branch points with, in some embodiments,functionality greater than three. The second type includes the followingstructure:

In Structure I, the horizontal chain symbolizes the polymer backbonechain, for example, a poly(n-butyl methacrylate) chain, and verticalchains symbolize side chains connected to the backbone chain. Oneexample of a polymer that can form side chains is poly(ethylene glycol).

A “linear polymer” is a polymer that does not contain branches with achain length greater than 3.

In some embodiments, a thermoplastic polymer is a polymer that may notbe capable of forming cross-links, and consequently does not formcrosslinks when heated, whether with or without a crosslinking catalyst.A thermoplastic polymer that includes cross linking fragments can becrosslinked. Examples of such fragments include π-bonds and functionalgroups, such as amino, epoxy, urethane, etc. Non crosslinkingthermoplastic polymers soften and fuse when heated and solidify whencooled. This melt-freeze cycle can be repeated many times withoutsubstantially chemically altering the polymer. Also, a solvent-solublethermoplastic polymer remains soluble after any number of melt-freezecycles.

Polymers that are linear and thermoplastic are “linear thermoplasticpolymers.” For the purposes of the present application, whenever theterms “linear polymer,” or “thermoplastic polymer,” or “linearthermoplastic polymer” are used, in some embodiments these termsspecifically exclude polymers that contain crosslinks. In someembodiments, “linear polymers” and “thermoplastic polymers” aresubstantially free of crosslinked fragments; in some embodiments,completely free of crosslinked fragments.

EMBODIMENTS

According to embodiments of the present invention, the composition caninclude a structural component comprising linear acrylic homopolymers orcopolymers or styrene, which, in some embodiments can be thermoplastic;and a biobeneficial component comprising copolymers having an acrylatemoiety and a biobeneficial or bioactive moiety. The structural componentand the biobeneficial component can be blended. In some embodiments, thetwo components can be bonded, linked such as by a linking agent,conjugated or cross-linked. The mass ratio between the structuralcomponent and the biobeneficial component can be between about 99:1 andabout 1:1, more narrowly, between about 19:1 and about 9:1, for example,about 3:1. In the biobeneficial component, the mass ratio between theacrylate moiety and the biobeneficial moiety can be between about 99:1and about 1:1, more narrowly, between about 19:1 and about 9:1, forexample, about 3:1.

Structural Component

The biologically compatible structural component can comprise linearacrylic homopolymers or copolymers, for example. In some embodiment, thehomo- and co-polymers can be thermoplastic. The structure of linearacrylic homopolymers and copolymers can be illustrated by generalFormula I.

wherein X can be hydrogen or methyl group; each of R and R₁ canindependently be methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, lauryl, or 2-hydroxyethyl; m is apositive integer, and n can be 0 or a positive integer. If n=0, thepolymer represented by Formula I is an acrylic homopolymer, and if n≠0,the polymer represented by Formula I is an acrylic copolymer.

A linear acrylic homopolymer corresponding to Formula I can be obtainedby polymerizing one acrylic monomer, CH₂═CX-M, using common techniques.To obtain a linear acrylic copolymer corresponding to Formula I, two ormore acrylic monomers, CH₂═CX-M, can be copolymerized. Any combinationof acrylic monomers can be used to prepare a linear acrylic copolymeraccording to Formula I. Examples of CH₂═CX-M monomers that can be usedare shown in Table 1.

TABLE 1 Abbre- via- No. Monomer tion X M 1 Methyl- methacrylate MMA CH₃

2 Ethyl- methacrylate EMA CH₃

3 n-Propyl methacrylate PMA CH₃

4 iso- Propyl- methacrylate i-PMA CH₃

5 n-Butyl- methacrylate BMA CH₃

6 n- Lauryl- methacrylate LMA CH₃

7 2- Hydroxy- ethyl- methacrylate HEMA CH₃

One example of a linear acrylic homopolymer suitable for the structuralcomponent is poly(n-butyl methacrylate) (PBMA). The structure of PBMAcorresponds to Formula I, where X═CH₃, R=n-C₄H₉, and n=0. PBMA is athermoplastic homopolymer. Examples of linear acrylic copolymerssuitable for the structural component includepoly(methylmethacrylate-co-2-hydroxyethyl methacrylate) (PMMA-HEMA) andpoly(n-butylmethacrylate-co-2-hydroxyethyl methacrylate) (PBMA-HEMA).Other homopolymers or copolymers described by Formula I, or mixturesthereof can be also used.

Biobeneficial Component

The biobeneficial component can comprise a copolymer having at least oneacrylate moiety and at least one biobeneficial moiety. In someembodiments, random, block, graft or brush copolymers can be used. Forrandom copolymers, some constituent units of the copolymers can includean acrylate moiety while other constituent units can include abiobeneficial moiety.

Examples of useful block copolymers include AB-, ABA-, BAB-, ABC-, orABCBA block copolymers. For AB-, ABA- or BAB-block copolymers, eithermoiety A or B can be an acrylate moiety, and the other moiety can be abiobeneficial moiety. Similarly, for an ABC block copolymer, eithermoiety A, B, or C, or any two of A, B, and C can be an acrylate moietyor moieties, while the remaining moiety or moieties can bebiobeneficial.

One example of a block copolymer that can be used is illustrated byFormula II:

wherein:

(a) m₁, n₁, p₁, r₁, m₂, n₂, p₂, and r₂ are all integers, wherein m₁≧0,n₁>0, p₁≧0, r₁>0; m₂≧0, n₂>0, p₂≧0, r₂>0; and if m₁=0, then p₁>0, and ifp₁=0, then m₁>0; and if m₂=0, then p₂>0, and if p₂=0, then m₂>0; and r₁and r₂ can be the same or different; m₁ and m₂ can be the same ordifferent; n₁ and n₂ can be the same or different; and p₁ and p₂ can bethe same or different;

(b) X can be hydrogen or methyl group;

(c) each of R and R₁ can be methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, lauryl, 2-hydroxyethyl; and

(d) B-units are biobeneficial moieties, which can be attached to thebackbone of the block copolymer in a variety of ways, for example by anacyl group or by a methylene bridge. Q makes the B-units biobeneficial,

If a random copolymer is used as the biobeneficial component, thestructure of the random copolymer is generally similar to the structureshown in Formula II, except the A-, B-, and C-units in the randomcopolymer are randomly distributed.

Examples of Q providing biobeneficial properties to the B-units includethose derived from poly(alkylene glycols) such as poly(ethylene glycol),polypropylene glycol), poly(tetramethylene glycol), poly(ethyleneglycol-co-propylene glycol), or poly(ethylene oxide-co-propylene oxide),superoxide dismutate-mimetics (SODm), diazenium diolate type nitricoxide donors, polycationic peptides, polysaccharides, for example,heparin or heparin derivatives, pyrrolidone, vitamin E, sulfonateddextrane, β-phenoxyethanol, N,N-dimethylamino-2-ethanol,mannose-6-phosphate, sulfonic acid and derivatives of sulfonic acid suchas propanesulfonic acid, 2-methyl-1-propanesulfonic acid,benzenesulfonic acid, and 3-methoxy-2-hydroxypropanesulfonic acid.

Superoxide dismutate-mimetics (SODm) are oxidoreductase-based complexesthat contain of copper, iron, or manganese cations. SODm are majorintracellular enzymes that protect the cell from oxygen toxicity bydismutating the superoxide, radical O₂—, to oxygen and hydrogenperoxide. A hepta coordinated, manganese-based SODm, manganese(II)dichloroaminoethylthiolated pentaazatetracyclohexacosatriene (SOD-40470)(manufactured by Metaphore Pharmaceuticals, Inc., St. Louis, Mo.) is oneexample of SODm that can be used in B-units. Other types of SODm canalso be used, if desired. Diazeniumdiolate-type nitric-oxide donors areadducts of nitric oxide (NO) with nucleophilic amines. Diazeniumdiolates, also known as NONOates, are highly biologically compatible andpossess valuable medicinal properties. In slightly acidic medium, theyspontaneously release NO, which has excellent therapeutic properties.One example of diazenium diolate that can be used for making B-units isan aliphatic NONOate, 1,3-propanediamine,N-{4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl}-diazen-1-ium-1,2-diolate,also known as speramine diazenium diolate (SDD) and having the formulaNH2-(CH₂)₃—N[N+(O)—(N—OH)]—(CH₂)₄—NH—(CH₂)₃—NH₂. SDD is manufactured byMolecular Probes, Inc., Eugene, Oreg. Alternatively, other diazeniumdiolate-type NO donors can be used. One example of a suitable diazeniumdiolatetype NO donor is1-{N-methyl-N-[6-(N-methylammonio)hexyl]amino}diazen-1-ium-1,2-diolatehaving the formula CH₃—N+H₂—(CH₂)₆—N(CH₃)—N+(O—)═N—O-(MAHMA-NO). Anotherexample of a suitable alternative NONOate is andZ-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolatehaving the formula O—N+[N(CH₂—CH₂—NH₂)CH₂—CH₂—N+H₃]═N—O-DETA-NO).MAHMA-NO and DETA-NO can be obtained from Cayman Chemical Co., AnnArbor, Mich.

Examples of polycationic peptides that can be used to make B-unitsinclude poly(L-arginine), poly(D-arginine), poly(D,L-arginine),poly(L-lysine), poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid),and a racemic mixture of poly(L-arginine) or poly(D-arginine). The terms“poly(L-arginine)”, “poly(D-arginine)”, “poly(D,L-arginine)” includesL-, D-, and/or D,L-arginine in both its polymeric and oligomeric form.

Heparin derivates can be used for the B-units, as well. Heparin isderived from a mixture of sulfated polysaccharide chains based onD-glucosamine and D-glucoronic or L-iduronic acid. In some embodiments,“heparin derivative” include any functional or structural variation ofheparin. Representative variations include heparinoids, heparin having ahydrophobic counterion, heparan sulfate, alkali metal or alkaline-earthmetal salts of heparin, for example, sodium heparin (also known ashepsal or pularin), potassium heparin (formerly known as clarin),lithium heparin, calcium heparin (also known as calciparine), magnesiumheparin (also known as cutheparine), low molecular weight heparin (alsoknown as ardeparin sodium), and blends thereof. Alternatively, someembodiments define “heparin derivatives” to specifically exclude any oneor any combination of heparinoids, heparin having a hydrophobiccounterion, heparan sulfate, alkali metal or alkaline-earth metal saltsof heparin, sodium heparin (also known as hepsal or pularin), potassiumheparin (formerly known as clarin), lithium heparin, calcium heparin(also known as calciparine), magnesium heparin (also known ascutheparine), or low molecular weight heparin (also known as ardeparinsodium).

Examples of other B-unit-suitable polysaccharides includeglycosaminoglycans (or mucopolysaccharides) such as keratan sulfate,chondroitin sulfate, dermatan sulfate (also known as chondroitin sulfateB), hyaluronic acid, hyaluronates and blends thereof.

The acrylate moiety forming a part of the random or block copolymer (A-and/or C-units shown in Formula II) can be derived from CH₂═CX-Macrylates. For example, any monomer shown in Table 1 can be used.

The biobeneficial moiety forming the random or block copolymer (B-unitsin Formula II) from unsaturated monomers or oligomers. The choice of themonomer or oligomer depends on the desired biological response. Forexample, the biobeneficial moiety can be anti-restenotic or can ensurebetter blood compatibility, or can promote cell adhesion.

Examples of the monomers or oligomers yielding antirestenotic moietiescan be derived include acryloyl-, methacryloyl-, vinyl or allyl-modifiedadducts of SODm, acryloyl-, methacryloyl-, vinyl or allyl-modified NOdonors examples of NO donors include DETA or speramine), acryloyl-,methacryloyl-, vinyl or allyl-modified adducts of phosphoryl choline,and acryloyl-, methacryloyl-, vinyl or allyl-modified polycationicpeptides such as poly-L-arginine.

Examples of monomers that can form the biobeneficial moiety include2-acrylamido-2-methyl-1-propanesulfonic acid, poly(ethylene glycol)methacrylate, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate,N-vinylpyrrolidone, vinylsulfonic acid, 4-styrenesulfonic acid and3-allyloxy-2-hydroxypropanesulfonic acid. All monomers based on sulfonicacid can be either alkali metal salts (e.g., K+ or Na+) or acids.

Turning again to the polymeric structure represented by Formula II, someexamples of particular copolymers having that structure that can be usedinclude poly(ethyleneglycol)-block-poly(n-butylmethacrylate)-block-poly(ethylene glycol)(PEG-PBMA-PEG, an ABA block copolymer), orpoly(n-butylmethacrylate)-block-poly(ethyleneglycol)-block-poly(n-butylmethacrylate) (PBMA-PEG-PBMA, a BAB-blockcopolymer). In both PEG-PBMA-PEG and PBMA-PEG-PBMA, the molecular weightof the PEG units can be between about 500 and 30,000 Daltons, and themolecular weight of the PBMA units can be between about 500 and 30,000Daltons.

The random or block copolymers represented by Formula II can be obtainedby common synthetic methods, for example, by radical copolymerization ofmonomers forming A-, B-, and/or C-units in bulk, solution, suspension,or emulsion with of suitable initiators.

For preparing random copolymers, standard radical-polymerizationinitiators can be used. Examples of suitable initiators includeazobis(isobutyronitrile) and 2,2-dimethoxy-2-phenol acetophenone.Optionally, the photosensitizer, benzophenone, can be added to2,2-dimethoxy-2-phenol acetophenone.

Living, free-radical copolymerization followed byinitiation-transfer-agent termination of the living polymer chains (theinferter process) can yield inventive block copolymers. The inferterprocess uses an initiator that exhibits thermal photolytic free-radicaldecomposition. Examples of these initiators arebenzyl-N,N-diethyldithiocarbamate (BDC) orp-xylylene-N,N-diethyldithiocarbamate (XDC). BDC is a toluene derivativeand has the formula shown in Formula III:

XDC is a p-xylene derivative and has the formula shown in Formula IV:

BDC or XDC initiators can be synthesized by combining sodiumN,N-diethyldithiocarbamate with benzyl bromide in an anhydrous methanolsolution. Some embodiments use an equimolar or substantially equimolarratio. The mixture can be stirred for about 24 hours at about roomtemperature to yield BDC solution. The solution can be removed byevaporating methanol at a reduced pressure or by vacuum distillation.The synthesis of XDC is similar, except, α,α-dibromo-p-xylene replacesbenzyl bromide, and the molar ratio between sodiumN,N-diethyldithiocarbamate and α,α-dibromo-p-xylene can rise to about1:2.3. This yields XDC, which can be purified by recrystallization inmethanol.

Optional Component

In some embodiments, other polymers can be added to composition. Thiscan be in a form of a simple blend or a linking, conjugation or bondingprocess. Representative examples include poly(ethylene-co-vinylalcohol), poly(hydroxyvalerate), poly(L-lactic acid), polycaprolactone,poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolicacid-co-trimethylene carbonate), poly(glycerol-sebacate),polyphosphoester, polyphosphoester urethane; poly(amino acids),cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates,polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, vinyl halide polymers and copolymers (such as polyvinylchloride), polyvinyl ethers (such as polyvinyl methyl ether),polyvinylidene halides (such as polyvinylidene fluoride andpolyvinylidene chloride), polyacrylonitrile, polyvinyl ketones,polyvinyl aromatics (such as polystyrene), polyvinyl esters (such aspolyvinyl acetate), copolymers of vinyl monomers with each other andolefins (such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers), polyamides (such as Nylon 66 and polycaprolactam), alkydresins, other polycarbonates, polyoxymethylenes, polyimides, polyethers,epoxy resins, other polyurethanes, rayon, rayon-triacetate, cellulose,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,soluble fluorinated polymers and carboxymethyl cellulose.

In addition to or in lieu of another polymer, a drug or therapeuticagent can serve as the optional component. The therapeutic agent caninclude any substance capable of exerting a therapeutic, diagnostic orprophylactic effect for a patient. The therapeutic agent may includesmall molecules, peptides, proteins, oligonucleotides, and the like. Thetherapeutic agent could be designed, for example, to inhibit thevascular-smooth-muscle-cell activity. It can inhibit abnormal orinappropriate migration or proliferation of smooth muscle cells.Examples of therapeutic substances that can be used includeantiproliferative substances such as actinomycin D, or derivatives andanalogs thereof (manufactured by Sigma-Aldrich of Milwaukee, Wis., orCOSMEGEN available from Merck). Synonyms of actinomycin D includeactinomycin, actinomycin IV, actinomycin I1, actinomycin X1, andactinomycin C1. The active agent can also fall under the genus ofantineoplastic, antiinflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, antiallergic andantioxidant substances. Examples of such antineoplastics and/orantimitotics include paclitaxel (e.g. TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g. Taxotere®, from Aventis S.A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as ANGIOMAX (Biogen, Inc., Cambridge, Mass.). Examplesof cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, tacrolimus, dexamethasone, and rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUSavailable from Novartis), 40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

Medial Device Application

A medical device can be made from the composition or coated with thecomposition. The device can include any medical device, preferablyimplantable medical devices such as catheters, balloons, guidewires,stents, grafts, stent-grafts, intra-ocular lenses, artificial heartvalves, cerebrospinal fluid shunts, pacemaker electrodes, andendocardial leads. The underlying structure of the device can be ofvirtually any design. The device can be made of a metallic material oran alloy such as, but not limited to, cobalt chromium alloy (ELGILOY),stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE (Nitinol),tantalum, nickel-titanium alloy, platinum-iridium alloy, gold,magnesium, or mixtures thereof. “MP35N” and “MP20N” are trade names foralloys of cobalt, nickel, chromium and molybdenum available fromStandard Press Steel Co. of Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention. In one example, the device isa bioabsorbable or erodable stent.

Stents

The embodiments of the present invention can be used as a coating for astent. The stent can include a primer layer; a drug-polymer layer (alsoreferred to as “reservoir” or “reservoir layer”) or alternatively apolymer-free drug layer; a topcoat layer; and a finishing coat layer.The top coat layer or the primer layer can be free from any drugs. Somedrugs may migrate into these layers during or subsequent to themanufacturing process. Any one or combination of the coating layers canbe formed on the stent by dissolving the composition of the presentinvention in a solvent, or a solvent mixture, and applying the solutionto the stent by spraying or immersion. The removal of the solvent canproduce a dry coating. Elevating the temperature can accelerate drying.The complete coating can be annealed between about 40 and about 150° C.for about 5 to about 60 minutes, if desired, to improve the coating'sthermal stability. To incorporate a drug into the reservoir layer, thedrug can be combined with the polymer solution.

A stent having the above-described coating is useful for a variety ofmedical procedures, including, by way of example, treatment ofobstructions caused by tumors in bile ducts, esophagus, trachea/bronchiand other biological passageways. A stent having the above-describedcoating is particularly useful for treating occluded regions of bloodvessels caused by abnormal or inappropriate migration and proliferationof smooth muscle cells, thrombosis, and restenosis. Stents may be placedin a wide array of blood vessels, both arteries and veins.Representative examples of sites include the iliac, renal, and coronaryarteries.

The compositions of the invention can be used for the treatment of avariety of disorder in mammals including atherosclerosis, thrombosis,restenosis, hemorrhage, vascular dissection or perforation, vascularaneurysm, vulnerable plaque, chronic total occlusion, claudication,anastomotic proliferation for vein and artificial grafts, bile ductobstruction, ureter obstruction, tumor obstruction, cancer as well asother disorders.

Embodiments of the present invention are further illustrated by thefollowing examples. Throughout the examples section and throughout thespecification and claims, for economy of language “solvent” means puresolvents and systems of mixtures of solvents.

Example 1 Synthesis of a Random Copolymer

A solution comprising a blend of monomers, a thermal initiator, and asolvent can be prepared by thoroughly mixing the following components:

(a) about 25 mass % of a first monomer, methylmethacrylate (MMA);

(b) about 19 mass % of a second monomer, n-butylmethacrylate (BMA);

(c) about 8 mass % of a third monomer, poly(ethyleneglycol)-methacrylate (PEGMA), where PEG can have weight-averagemolecular weight of about 6,000;

(d) between about 0.5 mass % and about 3.0 mass %, for example, about1.5 mass % of a thermal initiator, azobis-iso-butyronitrile (AIBN); and

(e) the balance of a solvent such as benzene.

AIBN is an example of a useful thermal initiator. Those having ordinaryskill in the art know of others, for example, peroxide-type initiators,as well.

Thermal radical copolymerization can be carried between about 50 andabout 60° C. for an amount of time, for example, for about 2 hours. Theprocess can be carried out in an inert atmosphere, such as that createdby bubbling an inert gas such as nitrogen or argon through the solutionfor about 30 minutes. At 50-60° C., AIBN decomposes, releasing nitrogenand generating free radicals.

These free radicals then react with MMA, BMA, and PEGMA that are presentin the blend, initiating and propagating radical copolymerization,yielding a random copolymer, poly(methyl methacrylate-co-n-butylmethacrylate-co-poly(ethylene glycol)-methacrylate) or P(MMA-BMA-PEGMA).One possible structure of P(MMA-BMA-PEGMA) is shown by Formula V:

Optionally, P(MMA-BMA-PEGMA) can be obtained with a UV-initiatedprocess. To conduct this process, a solution comprising a blend of BMA,MMA and PEGMA in benzene can be prepared, as described above. Aphotoinitiator, e.g., 2,2-dimethoxy-2-phenol acetophenone, can bedissolved in the solution instead of AIBN. The amount of2,2-dimethoxy-2-phenol acetophenone can be the same as described above.The solution can then be exposed to UV radiation for about 10 minutes ata wavelength of 360 nm while being stirred yielding P(MMA-BMA-PEGMA),Formula V.

Example 2 Synthesis of an ABA-Block Copolymer

As a first step, n-butylmethacrylate (BMA) can be dissolved in2-butanone and an initiator, XDC, can be added. Component amounts aresummarized in Table 2.

TABLE 2 Amount No. Component mmol g 1 BMA 140.700 19.98 2 2-butanone —59.41 3 XDC 0.287 0.1151

The solution of BMA and XDC in 2-butanone can be placed into aborosilicate vial, purged with dry nitrogen for about 30 minutes, andthe vial can be sealed. The contents can be UV irradiated at awavelength of about 310 and about 400 nm, for about 12 hours. The vialcan then be opened, and the contents can be added dropwise to ethanol−76° C. As a result, poly(butylmethacrylate)-XDC adduct (PBMA-XDC) canbe precipitated, collected, and vacuum dried using a vacuum funnel.

Next, PBMA-XDC can be combined with acryloyl poly(ethylene glycol)(acryloyl-PEG) and 2-butanone in the amounts shown in Table 3.

TABLE 3 Amount No. Component mmol g 1 PBMA-XDC 0.0064 1.00 2 2-butanone— 12.40 3 Acryloyl-PEG 0.625 0.25

Acryloyl-PEG is a PEG esterification product of acrylic acid and has aFormula VI:

A low molecular weight acryloyl-PEG oligomer, with a number-averagemolecular weight (Mn) of about 375, can be used. This corresponds to avalue of x in Formula VI of about 7. The blend of PBMA-XDC, acryloyl-PEGand 2-butanone can be UV irradiated at a wavelength of about 310 toabout 400 nm, for about 12 hours. The vial can then be opened, and thecontents can be added dropwise to water and vigorously stirred at about70° C. for about 2 hours, evaporating the 2-butanone and suspending thepoly(acryloyl-PEG)-block-n-butylmethacrylate-block-acryloyl-PEG)-XDC.The suspension can be cooled to room temperature, and the precipitatecan be collected and vacuum dried using a vacuum funnel. The adduct isthen hydrolyzed in the presence of a strong base to remove XDC. As aresult, poly(acryloyl-PEG-block-n-butylmethacrylate-block-acryloyl-PEG)(PEG-PBMA-PEG), which is a ABA-block copolymer having Formula VII, canbe precipitated.

Example 3 Synthesis of an AB Block Copolymer

First, a PBMA-XDC adduct can be obtained from Example 2. Second,PBMA-XDC can be combined with acryloyl poly(ethylene glycol)(acryloyl-PEG) and 2-butanone in the amounts shown in Table 4.

TABLE 4 Amount No. Component mmol g 1 PBMA-XDC 0.0032 0.50 2 2-butanone— 12.40 3 Acryloyl-PEG 0.625 0.25

A low-molecular-weight acryloyl-PEG oligomer, with a number-averagemolecular weight (Mn) of about 375, can be used. This corresponds to avalue of x in Formula VII of about 7. The blend of PBMA-XDC,acryloyl-PEG and 2-butanone can be UV radiated at a wavelength of about310 to about 400 nm, for about 12 hours. The vial can then be opened,and the contents can be added dropwise to water and vigorously stirredat a about 70° C. for about 2 hours, evaporating the 2-butanone andsuspending the poly(n-butylmethacrylate-block-acryloyl-PEG)-XDC. Thesuspension can be cooled to room temperature and the precipitate can becollected and vacuum-dried. The adduct is then hydrolyzed in thepresence of a strong base to remove XDC, yieldingpoly(n-butylmethacrylate-block-acryloyl-PEG) (PBMA-PEG), which is anAB-block copolymer having Formula VIII.

Example 4 Synthesis of a Copolymer Containing Phosphoryl Choline Moiety

Equimolar amounts of n-butyl methacrylate (BMA), acryloyl-PEG, andacryloyl-phosphoryl choline can be mixed and dissolved in 2-butanone.Phosphoryl choline is also known as N,N,N-trimethyl-2-aminoethylphosphonate. Acryloyl-phosphoryl cho-line is an acrylic derivative ofphosphoryl choline having the Formula IX:

A low molecular weight acryloyl-PEG oligomer, with a number-averagemolecular weight (Mn) of about 375, can be used. This corresponds to avalue of x in Formula X of about 7. The blend of BMA, acryloyl-PEG,acryloyl-phosphoryl choline and 2-butanone can be UV radiated at awavelength of about 310 to about 400 nm, for about 12 hours. The vialcan then be opened, and the contents can be added dropwise to water andvigorously stirred at a about 70° C. for about 2 hours, evaporating the2-butanone and suspending thepoly(n-butylmethacrylate-co-acryloyl-PEG-co-acryloyl-phosphorylcholine). The suspension can be cooled to the room temperature, and theprecipitate can be collected and vacuum dried. As a result,poly(n-butylmethacrylate-co-acryloyl-PEG-co-acryloyl-phosphoryl choline)(PBMA-PEG-PC), can be obtained. One possible structure for PBMA-PEG-PCis shown by Formula X:

Example 5

A first composition can be prepared by mixing the following components:

(a) about 2.0 mass % PBMA; and

(b) the balance, a solvent blend of acetone and cyclohexanone in a massratio of about 7:3.

The first composition can be sprayed onto the surface of a bare 13 mmTETRA stent (available from Guidant Corporation), and dried to form aprimer layer. A spray coater can be used having a 0.014 fan nozzlemaintained at about 60° C. with a feed pressure of about 0.2 atm (about3 psi) and an atomization pressure of about 1.3 atm (about 20 psi). Theprimer layer can be baked at about 80° C. for about 30 minutes, yieldinga dry primer layer. The dry primer layer can contain about 60 μg ofPBMA.

A second composition can be prepared by mixing the following components:

(a) about 1.5 mass % PBMA;

(b) about 0.5 mass % PBMA-PEG block copolymer obtained as described inExample 3;

(c) about 1.0 mass % EVEROLIMUS; and

(d) the balance, DMAC as the solvent (alternatively, cyclohexanone canbe used as the solvent).

Overall, the second composition can contain about 600 μg of the mixture.It composition can be applied onto the dried primer layer to form areservoir layer, using the primer layer's spraying techniques andequipment. This is followed by drying, e.g., by baking at about 50° C.for about 2 hours, yielding a dry reservoir layer.

A third composition can be prepared by mixing the following components:

(a) about 2.0 mass % the PBMA-PEG block-polymer described in Example 3;and

(b) the balance, DMAC as the solvent (alternatively, cyclohexanone canbe used as the solvent).

The third composition can be applied onto the dried reservoir layer toform a topcoat layer using the same spraying technique and equipmentused for applying the primer layer and the reservoir layer. The wettopcoat layer can be dried and baked at about 50° C. for about 2 hours.The dry topcoat layer can contain about 200 μg of the PBMA-PEGblock-polymer.

Example 6

A primer layer can be fabricated as described in Example 5.

A first composition can be prepared by mixing the following components:

(a) about 1.5 mass % PBMA;

(b) about 0.5 mass % PBMA-PEG block copolymer obtained as described inExample 3;

(c) about 0.05 mass % PEG having molecular weight between about 4,000and about 100,000 Daltons; (up to 0.06 mass % of this PEG can be used inthis example)

(d) about 1.0 mass % EVEROLIMUS; and

(e) the balance, DMAC as the solvent (alternatively, cyclohexanone canbe used as the solvent).

Overall, the second composition can contain about 600 μg of the mixture.It can be applied onto the dried primer layer to form the reservoirlayer as described in Example 5.

A third composition can be prepared by mixing the following components:

(a) about 2.0 mass % the PBMA-PEG block-polymer described in Example 3;and

(b) the balance, DMAC as the solvent (alternatively, cyclohexanone canbe used as the solvent).

The third composition can be applied onto the dried reservoir layer toform a topcoat layer as described in Example 5.

Example 7

A primer layer can be fabricated as described in Example 5.

A first composition can be prepared by mixing the following components:

(a) about 1.5 mass % PBMA;

(b) about 0.5 mass % PBMA-PEG block copolymer obtained as described inExample 3;

(c) about 0.05 mass % PEG having molecular weight between about 4,000and about 100,000 Daltons; (up to 0.06 mass % of this PEG can be used inthis example)

(d) about 0.06 mass % Na heparin; (up to 2.5 mass % Na heparin)

(e) about 1.0 mass % EVEROLIMUS; and

(f) the balance, DMAC as the solvent (alternatively, cyclohexanone canbe used as the solvent).

Overall, the second composition can contain a about 600 μg of themixture. When Na heparin is used, the composition is not necessarily asolution because Na heparin is not completely soluble in the solvent. Itcan be applied onto the dried primer layer to form the reservoir layeras described in Example 5.

A third composition can be prepared by mixing the following components:

(a) about 2.0 mass % the PBMA-PEG block-polymer described in Example 3;and

(b) the balance, DMAC as the solvent (alternatively, cyclohexanone canbe used as the solvent).

The third composition can be applied onto the dried reservoir layer toform a topcoat layer as described in Example 5.

Example 8

A primer layer can be fabricated as described in Example 5.

A first composition can be prepared by mixing the following components:

(a) about 1.5 mass % PBMA;

(b) about 0.5 mass % PBMA-PEG block copolymer obtained as described inExample 3;

(c) about 0.05 mass % PEG having molecular weight between about 4,000and about 100,000 Daltons; (up to 0.06 mass % of this PEG can be used inthis example)

(d) about 0.06 mass % hydrophobic quaternized heparin; (up to 2.5 mass %hydrophobic quaternized heparin)

(e) about 1.0 mass % EVEROLIMUS; and

(f) the balance, DMAC as the solvent (alternatively, cyclohexanone canbe used as the solvent).

Overall, the second composition can contain a about 600 μg of themixture. It can be applied onto the dried primer layer to form thereservoir layer as described in Example 5.

A third composition can be prepared by mixing the following components:

(a) about 2.0 mass % the PBMA-PEG block-polymer described in Example 3;and

(b) the balance, DMAC as the solvent (alternatively, cyclohexanone canbe used as the solvent).

The third composition can be applied onto the dried reservoir layer toform a topcoat layer as described in Example 5.

Example 9

A primer layer and a reservoir layer can be fabricated as described inExample 5.

A composition can be prepared by mixing the following components:

(a) about 2.0 mass % POLYACTIVE copolymer; and

(b) the balance, a solvent blend of 1,1,2-tricloroethane and chloroformin a mass ratio between 1,1,2-tricloroethane and chloroform of about4:1.

POLYACTIVE is a trade name of a family of poly(ethyleneglycol)-block-poly(butyleneterephthalate)-block poly(ethylene glycol)copolymers (PEG-PBT-PEG) and is available from IsoTis Corp. of Holland.The grade of POLYACTIVE that can be used can have about 45 molar % unitsderived from PBT and about 55 molar % units derived from PEG. Themolecular weight of the PEG units can be about 300 Daltons. The overallweight-average molecular weight (Mw) of POLYACTIVE can be between about75,000 Daltons and about 125,000 Daltons.

The composition can be applied onto the dried reservoir layer to form atopcoat layer as described in Example 5.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

Embodiments of the present invention also include the following:

1. A composition comprising:

-   -   (a) a biologically compatible structural component comprising a        linear acrylic homopolymer or a linear acrylic copolymer; and    -   (b) a biobeneficial component comprising a copolymer having a an        acrylate moiety and a biobeneficial moiety.        2. The composition of embodiment 1, coated onto an implantable        medical device.        3. The composition of embodiment 1, wherein the mass ratio        between the structural component and the biobeneficial component        is between about 99:1 and about 1:1.        4. The composition of embodiment 1 wherein the mass ratio        between the structural component and the biobeneficial component        is between about 19:1 and about 9:1.        5. The composition of embodiment 1, wherein the mass ratio        between the structural component and the biobeneficial component        is about 3:1.        6. The composition of embodiment 1, wherein the acrylic        homopolymer or linear acrylic copolymer has the structure:

wherein

-   -   (c) X is hydrogen or methyl group;    -   (d) each of R and R₁ is independently methyl, ethyl, n-propyl,        iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, lauryl,        or 2-hydroxyethyl;    -   (e) m is a positive integer; and    -   (f) n is 0 or a positive integer.        7. The composition of embodiment 1, wherein the acrylic        homopolymer or linear acrylic copolymer is        poly(methylmethacrylate), poly(ethylmethacrylate), poly(n-propyl        methacrylate), poly(iso-propylmethacrylate),        poly(n-butylmethacrylate), poly(n-laurylmethacrylate),        poly(2-hydroxyethylmethacrylate),        poly(methylmethacrylate-co-2-hydroxyethyl methacrylate),        poly(n-butylmethacrylate-co-2-hydroxyethyl methacrylate), or        mixtures thereof.        8. The composition of embodiment 1, wherein the biobeneficial        component includes random, block, graft or brush copolymers.        9. The composition of embodiment 8, wherein the block copolymers        include AB-, ABA-, BAB-, ABC-, or ABCBA-block copolymers.        10. The composition of embodiment 1, wherein the biobeneficial        moiety includes fragments derived from poly(alkylene glycols),        superoxide dismutate-mimetics (SODm), diazenium diolate type        nitric oxide donors, polycationic peptides, polysaccharides,        pyrrolidone, vitamin E, sulfonated dextrane, β-phenoxyethanol,        N,N-dimethylamino-2-ethanol, mannose-6-phosphate, sulfonic acid,        derivatives of sulfonic acid, or mixtures thereof.        11. The composition of embodiment 10, wherein the poly(alkylene        glycols) are poly(ethylene glycol), poly(propylene glycol),        poly(tetramethylene glycol), poly(ethylene glycol-co-propylene        glycol), poly(ethylene oxide-co-propylene oxide), or mixtures        thereof        12. The composition of embodiment 10, wherein the polycationic        peptides are poly(L-arginine), poly(D-arginine),        poly(D,L-arginine), poly(L-lysine), poly(D-lysine),        poly(δ-guanidino-α-aminobutyric acid), a racemic mixture of        poly(L-arginine) or poly(D-arginine), or mixtures thereof.        13. The composition of embodiment 10, wherein the        polysaccharides are heparin or derivatives thereof,        glycosaminoglycans, keratan sulfate, chondroitin sulfate,        dermatan sulfate, hyaluronic acid, hyaluronates, or mixtures        thereof        14. The composition of embodiment 13, wherein the derivatives of        heparin are heparinoids, heparin having a hydrophobic        counterion, heparan sulfate, heparin salts, or mixtures thereof        15. The composition of embodiment 14, wherein the heparin salts        are sodium heparin, potassium heparin, lithium heparin, calcium        heparin, magnesium heparin, adrenalin sodium, or mixtures        thereof        16. The composition of embodiment 10, wherein the derivatives of        sulfonic acid are propane-sulfonic acid,        2-methyl-1-propanesulfonic acid, benzenesulfonic acid,        3-methoxy-2-hydroxypropanesulfonic acid, or mixtures thereof.        17. The composition of embodiment 1, wherein the mass ratio        between the acrylate moiety and the biobeneficial moiety is        between about 99:1 and about 1:1.        18. The composition of embodiment 1, wherein the mass ratio        between the acrylate moiety and the biobeneficial moiety is        between about 19:1 and about 9:1        19. The composition of embodiment 1, wherein the mass ratio        between the acrylate moiety and the biobeneficial moiety is        about 3:1.        20. The composition of embodiment 1, wherein the copolymer        composing the biobeneficial component has the formula:

wherein

-   -   (g) m₁, n₁, p_(h) r₁, m₂, n₂, p₂, and r₂ are all integers;    -   (h) m₁≧0, n₁>0, p₁≧0, r₁>0; m₂≧0, n₂>0, p₂≧0, r₂>0; and    -   (i)        -   (i) if m₁=0, then p₁>0;        -   (ii) if p₁=0, then m₁>0; and        -   (iii) if m₂=0, then p₂>0; and        -   (iv) if p₂=0, then m₂>0; and        -   (v) r₁ and r₂ are the same or different;        -   (vi) m₁ and m₂ are the same or different;        -   (vii) n₁ and n₂ are the same or different; and        -   (viii) p₁ and p₂ are the same or different;    -   (j) X is hydrogen or methyl group;    -   (k) each of R, R₁ and R₂, independently, is methyl, ethyl,        n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,        lauryl, or 2-hydroxyethyl; and    -   (l) Q is a fragment providing the copolymer with biobeneficial        or bioactive properties.        21. The composition of embodiment 1, wherein the copolymer        composing the biobeneficial component is poly(ethylene        glycol)-block-poly(n-butylmethacrylate)-block-poly(ethylene        glycol), poly(n-butylmethacrylate)-block-poly(ethylene        glycol)-block-poly(n-butylmethacrylate), or mixtures thereof.        22. The composition of embodiment 1, wherein the biobeneficial        component includes a random, block, graft or brush copolymer        comprising:

-   -   (m) at least one of and

-   -   (n) at least one of

wherein

-   -   (o) X is hydrogen or methyl group;    -   (p) R is methyl, ethyl, n-propyl, iso-propyl, n-butyl,        sec-butyl, iso-butyl, tert-butyl, lauryl, or 2-hydroxyethyl; and    -   (q) Q is a fragment providing the copolymer with biobeneficial        properties.        23. The composition of embodiment 22, wherein the biobeneficial        component copolymer further comprises at least one of

wherein Q₂ is a fragment providing the copolymer with biobeneficial orbioactive properties provided that Q₂ is different from Q.

24. The composition of embodiment 22, wherein Q is derived frompoly(alkylene glycols), superoxide dismutate-mimetics (SODm), diazeniumdiolate type nitric oxide donors, polycationic peptides,polysaccharides, pyrrolidone, vitamin E, sulfonated dextrane,β-phenoxyethanol, N,N-dimethylamino-2-ethanol, mannose-6-phosphate,sulfonic acid, derivatives of sulfonic acid, or mixtures thereof.25. The composition of embodiment 24, wherein the polycationic peptidesare poly(L-arginine), poly(D-arginine), poly(D,L-arginine),poly(L-lysine), poly(D-lysine), poly(δ-guanidino-α-aminobutyric acid), aracemic mixture of poly(L-arginine) or poly(D-arginine), or mixtures ofthese.26. The composition of embodiment 24, wherein the polysaccharides areheparin or derivatives thereof, glycosaminoglycans, keratan sulfate,chondroitin sulfate, dermatan sulfate, hyaluronic acid, hyaluronates, orblends thereof.27. The composition of embodiment 24, wherein the derivatives of heparinare heparinoids, heparin having a hydrophobic counterion, heparansulfate, heparin salts, or mixtures thereof28. The composition of embodiment 24, wherein the derivatives ofsulfonic acid are propane-sulfonic acid, 2-methyl-1-propanesulfonicacid, benzenesulfonic acid, 3-methoxy-2-hydroxypropanesulfonic acid, ormixtures thereof.29. A medical article comprising an implantable medical device and acoating deposited on at least a part of the device, the coatingincluding:

-   -   (a) a structural component comprising a linear acrylic        homopolymer or linear acrylic copolymer; and    -   (b) a biobeneficial component comprising a copolymer having an        acrylate moiety and a biobeneficial moiety.        30. The medical article of embodiment 29, wherein the medical        device is a stent.        31. The medical article of embodiment 29, wherein the mass ratio        between the structural component and the biobeneficial component        is between about 99:1 and about 1:1.        32. The medical article of embodiment 29, wherein the acrylic        homopolymer or linear acrylic copolymer has the structure:

wherein

-   -   (c) X is hydrogen or methyl group;    -   (d) each of R and R₁ is independently methyl, ethyl, n-propyl,        iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, lauryl,        or 2-hydroxyethyl;    -   (e) m is a positive integer; and    -   (f) n is 0 or a positive integer.        33. The medical article of embodiment 29, wherein the copolymer        composing the biobeneficial component has the formula:

wherein

-   -   (g) m₁, n₁, p₁, r₁, m₂, n₂, p₂, and r₂ are all integers;    -   (h) m₁≧0, n₁>0, p₁≧0, r₁>0; m₂≧0, n₂>0, p₂≧0, r₂>0; and    -   (i)        -   (i) if m₁=0, then p₁>0;        -   (ii) if p₁=0, then m₁>0; and        -   (iii) if m₂=0, then p₂>0; and        -   (iv) if p₂=0, then m₂>0; and        -   (v) r₁ and r₂ are the same or different;        -   (vi) m₁ and m₂ are the same or different;        -   (vii) n₁ and n₂ are the same or different; and        -   (viii) p₁ and p₂ are the same or different;    -   (j) X is hydrogen or methyl group;    -   (k) each of R, R₁, and R₂, independently, is methyl, ethyl,        n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,        lauryl, or 2-hydroxyethyl; and    -   (l) Q is a fragment providing the copolymer with biobeneficial        properties.        34. The medical article of embodiment 29, wherein the copolymer        composing the biobeneficial component is poly(ethylene        glycol)-block-poly(n-butylmethacrylate)-block-poly(ethylene        glycol), or poly(n-butylmethacrylate)-block-poly(ethylene        glycol)-block-poly(n-butylmethacrylate).        35. The medical article of embodiment 29, wherein the        biobeneficial component includes a random, block, graft or brush        copolymer composed of:    -   (m) at least one of

and

-   -   (n) at least one of

wherein

-   -   (o) X is hydrogen or methyl group;    -   (p) R is methyl, ethyl, n-propyl, iso-propyl, n-butyl,        sec-butyl, iso-butyl, tert-butyl, lauryl, or 2-hydroxyethyl; and    -   (q) Q is a fragment providing the copolymer with biobeneficial        properties.        36. The medical article of embodiment 35, wherein Q is derived        from poly(alkylene glycols), superoxide dismutate-mimetics        (SODm), diazenium diolate type nitric oxide donors, polycationic        peptides, polysaccharides, pyrrolidone, vitamin E, sulfonated        dextrane, β-phenoxyethanol, N,N-dimethylamino-2-ethanol,        mannose-6-phosphate, sulfonic acid, derivatives of sulfonic        acid, or mixtures thereof.        37. The medical article of embodiment 36, wherein the        polycationic peptides are poly(L-arginine), poly(D-arginine),        poly(D,L-arginine), poly(L-lysine), poly(D-lysine),        poly(δ-guanidino-α-aminobutyric acid), a racemic mixture of        poly(L-arginine) or poly(D-arginine), or mixtures thereof.        38. The medical article of embodiment 36, wherein the        polysaccharides are heparin or derivatives thereof,        glycosaminoglycans, keratan sulfate, chondroitin sulfate,        dermatan sulfate, hyaluronic acid, hyaluronates, or mixtures        thereof.        39. The medical article of embodiment 36, wherein the        derivatives of heparin are heparinoids, heparin having a        hydrophobic counterion, heparan sulfate, heparin salts, or        mixtures thereof        40. The medical article of embodiment 36, wherein the        derivatives of sulfonic acid are propanesulfonic acid,        2-methyl-1-propanesulfonic acid, benzenesulfonic acid,        3-methoxy-2-hydroxypropanesulfonic acid, or mixtures thereof.        41. A method for fabricating a medical article comprising        depositing a polymeric blend comprising:    -   (r) a biologically compatible structural component; and    -   (s) a biobeneficial component comprising a copolymer having a        biobeneficial or bioactive moiety.

on at least a portion of the implantable medical device to form acoating.

42. The method of embodiment 41, wherein the implantable medical deviceis a stent.43. The method of embodiment 41, wherein the mass ratio between thestructural component and the biobeneficial component is between about99:1 and about 1:1.44. The method of embodiment 41, wherein the acrylic homopolymer orlinear acrylic copolymer have the structure:

wherein

-   -   (t) X is hydrogen or methyl group;    -   (u) each of R and R₁ is independently methyl, ethyl, n-propyl,        iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, lauryl,        or 2-hydroxyethyl;    -   (v) m is a positive integer; and    -   (w) n is 0 or a positive integer.        45. The method of embodiment 41, wherein the acrylic homopolymer        and linear acrylic copolymer are synthesized by polymerizing        monomers selected from a group consisting of methylmethacrylate,        ethylmethacrylate, n-propyl methacrylate,        iso-propylmethacrylate, n-butylmethacrylate,        n-laurylmethacrylate, 2-hydroxyethylmethacrylate, and mixtures        thereof.        46. The method of embodiment 41, wherein the step of preparing        the polymeric blend includes synthesizing the biobeneficial        random, block, graft or brush copolymers.        47. The method of embodiment 46, wherein the block copolymers        include AB-, ABA-, BAB-, ABC-, or ABCBA-block copolymers.        48. The method of embodiment 46, wherein the step of        synthesizing the block copolymers includes copolymerizing an        acrylate and a biobeneficial monomer by a method of living,        free-radical copolymerization with initiation-transfer agent        termination of the living macro chains.        49. The method of embodiment 48, wherein the acrylate is        methylmethacrylate, ethylmethacrylate, n-propyl methacrylate,        iso-propylmethacrylate, n-butylmethacrylate,        n-laurylmethacrylate, 2-hydroxyethylmethacrylate, or mixtures        thereof.        50. The method of embodiment 48, wherein the biobeneficial        monomer includes acryloyl-, methacryloyl-,vinyl, or        allyl-modified adducts of superoxide dismutate-mimetics;        acryloyl-, methacryloyl-, vinyl, or allyl-modified diazenium        diolate type nitric oxide donors; or acryloyl-, methacryloyl-,        vinyl, or allyl-modified polycationic peptides.        51. The method of embodiment 50, wherein the biobeneficial        monomer is 2-acrylamido-2-methyl-1-propanesulfonic acid,        poly(ethylene glycol) methacrylate, 3-sulfopropyl acrylate,        3-sulfopropyl acrylate methacrylate, N-vinylpyrrolidone, vinyl        sulfonic acid, 4-styrene sulfonic acid, or        3-allyloxy-2-hydroxypropanesulfonic acid.        52. The method of embodiment 41, wherein the biobeneficial        moiety includes fragments derived from poly(alkylene glycols),        superoxide dismutate-mimetics (SODm), diazenium diolate type        nitric oxide donors, polycationic peptides, polysaccharides,        pyrrolidone, vitamin E, sulfonated dextrane, β-phenoxyethanol,        N,N-dimethylamino-2-ethanol, mannose-6-phosphate, sulfonic acid,        derivatives of sulfonic acid, or mixtures thereof.        53. The method of embodiment 52, wherein the poly(alkylene        glycols) are poly(ethylene glycol), poly(propylene glycol),        poly(tetramethylene glycol), poly(ethylene glycol-co-propylene        glycol), poly(ethylene oxide-co-propylene oxide), or mixtures        thereof.        54. The method of embodiment 52, wherein the polycationic        peptides are poly(L-arginine), poly(D-arginine),        poly(D,L-arginine), poly(L-lysine), poly(D-lysine),        poly(δ-guanidino-α-aminobutyric acid), a racemic mixture of        poly(L-arginine) or poly(D-arginine), or mixtures thereof.        55. The method of embodiment 52, wherein the polysaccharides are        heparin, heparin derivatives, glycosaminoglycans, keratan        sulfate, chondroitin sulfate, dermatan sulfate, hyaluronic acid,        hyaluronates, or mixtures thereof.        56. The method of embodiment 55, wherein the derivatives of        heparin are heparinoids, heparin having a hydrophobic        counterion, heparan sulfate, heparin salts, or mixtures thereof.        57. The method of embodiment 56, wherein the heparin salts are        sodium heparin, potassium heparin, lithium heparin, calcium        heparin, magnesium heparin, ardeparin sodium, or mixtures        thereof.        58. The method of embodiment 52, wherein the derivatives of        sulfonic acid are propanesulfonic acid,        2-methyl-1-propanesulfonic acid, benzenesulfonic acid,        3-methoxy-2-hydroxypropane sulfonic acid, or mixtures thereof.        59. The method of embodiment 41, wherein the mass ratio between        the acrylate moiety and the biobeneficial moiety is between        about 99:1 and about 1:1.        60. The method of embodiment 41, wherein the mass ratio between        the acrylate moiety and the biobeneficial moiety is between        about 19:1 and about 9:1        61. The method of embodiment 41, wherein the mass ratio between        the acrylate moiety and the biobeneficial moiety is about 3:1.        62. The method of embodiment 41, wherein the copolymer        comprising the biobeneficial component has the formula:

wherein

-   -   (x) m₁, n₁, p₁, r₁, m₂, n₂, p₂, and r₂ are all integers;    -   (y) m₁≧0, n₁>0, p₁≧0, r₁>0; m₂≧0, n₂>0, p₂≧0, r₂>0; and    -   (z)        -   (i) if m₁=0, then p₁>0;        -   (ii) if p₁=0, then m₁>0; and        -   (iii) if m₂=0, then p₂>0; and        -   (iv) if p₂=0, then m₂>0; and        -   (v) r₁ and r₂ are the same or different;        -   (vi) m₁ and m₂ are the same or different;        -   (vii) n₁ and n₂ are the same or different; and        -   (viii) p₁ and p₂ are the same or different;    -   (aa) X is hydrogen or methyl group;    -   (bb) each of R, R₁, and R₂, independently, is methyl, ethyl,        n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,        lauryl, or 2-hydroxyethyl; and    -   (cc) Q is a fragment providing the copolymer with biobeneficial        properties.        63. The method of embodiment 41, wherein the copolymer        comprising the biobeneficial component is poly(ethylene        glycol)-block-poly(n-butylmethacrylate)-block-poly(ethylene        glycol), poly(n-butylmethacrylate)-block-poly(ethylene        glycol)-block-poly(n-butylmethacrylate), or mixtures thereof.

What is claimed is:
 1. A method for fabricating a medical articlecomprising depositing a polymeric blend comprising: (a) a biologicallycompatible structural component comprising a linear acrylic homopolymeror a linear acrylic copolymer, and (b) a biobeneficial componentcomprising a copolymer having an acrylate moiety and a biobeneficialmoiety, on at least a portion of the implantable medical device to forma coating.
 2. The method of claim 1, wherein the implantable medicaldevice is a stent.
 3. The method of claim 1, wherein the mass ratiobetween the structural component and the biobeneficial component isbetween about 99:1 and about 1:1.
 4. The method of claim 1, wherein thelinear acrylic homopolymer or linear acrylic copolymer have thestructure:

wherein (a) X is hydrogen or methyl group; (b) each of R and R₁ isindependently methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, lauryl, or 2-hydroxyethyl; (c) m is a positiveinteger; and (d) n is 0 or a positive integer.
 5. The method of claim 1,wherein the linear acrylic homopolymer and linear acrylic copolymer aresynthesized by polymerizing monomers selected from a group consisting ofmethylmethacrylate, ethylmethacrylate, n-propyl methacrylate,iso-propylmethacrylate, n-butylmethacrylate, n-laurylmethacrylate,2-hydroxyethylmethacrylate, and mixtures thereof.
 6. The method of claim1, wherein the step of preparing the polymeric blend includessynthesizing the biobeneficial random, block, graft or brush copolymers.7. The method of claim 6, wherein the block copolymers include AB-,ABA-, BAB-, ABC-, or ABCBA-block copolymers.
 8. The method of claim 6,wherein the step of synthesizing the block copolymers includescopolymerizing an acrylate and a biobeneficial monomer by a method ofliving, free-radical copolymerization with initiation-transfer agenttermination of the living macro chains.
 9. The method of claim 8,wherein the acrylate is methylmethacrylate, ethylmethacrylate, n-propylmethacrylate, iso-propylmethacrylate, n-butylmethacrylate,n-laurylmethacrylate, 2-hydroxyethylmethacrylate, or mixtures thereof.10. The method of claim 8, wherein the biobeneficial monomer includesacryloyl-, methacryloyl-,vinyl, or allyl-modified adducts of superoxidedismutate-mimetics; acryloyl-, methacryloyl-, vinyl, or allyl-modifieddiazenium diolate type nitric oxide donors; or acryloyl-, methacryloyl-,vinyl, or allyl-modified polycationic peptides.
 11. The method of claim10 wherein the biobeneficial monomer is2-acrylamido-2-methyl-1-propanesulfonic acid, poly(ethylene glycol)methacrylate, 3-sulfopropyl acrylate, 3-sulfopropyl acrylatemethacrylate, N-vinylpyrrolidone, vinyl sulfonic acid, 4-styrenesulfonic acid, or 3-allyloxy-2-hydroxypropanesulfonic acid.
 12. Themethod of claim 1, wherein the biobeneficial moiety includes fragmentsderived from poly(alkylene glycols), superoxide dismutate-mimetics(SODm), diazenium diolate type nitric oxide donors, polycationicpeptides, polysaccharides, pyrrolidone, vitamin E, sulfonated dextrane,β-phenoxyethanol, N,N-dimethylamino-2-ethanol, mannose-6-phosphate,sulfonic acid, derivatives of sulfonic acid, or mixtures thereof. 13.The method of claim 12, wherein the poly(alkylene glycols) arepoly(ethylene glycol), poly(propylene glycol), poly(tetramethyleneglycol), poly(ethylene glycol-co-propylene glycol), poly(ethyleneoxide-co-propylene oxide), or mixtures thereof.
 14. The method of claim12, wherein the polycationic peptides are poly(L-arginine),poly(D-arginine), poly(D,L-arginine), poly(L-lysine), poly(D-lysine),poly(δ-guanidino-α-aminobutyric acid), a racemic mixture ofpoly(L-arginine) or poly(D-arginine), or mixtures thereof.
 15. Themethod of claim 12, wherein the polysaccharides are heparin, heparinderivatives, glycosaminoglycans, keratan sulfate, chondroitin sulfate,dermatan sulfate, hyaluronic acid, hyaluronates, or mixtures thereof.16. The method of claim 15, wherein the derivatives of heparin areheparinoids, heparin having a hydrophobic counterion, heparan sulfate,heparin salts, or mixtures thereof.
 17. The method of claim 16, whereinthe heparin salts are sodium heparin, potassium heparin, lithiumheparin, calcium heparin, magnesium heparin, ardeparin sodium, ormixtures thereof.
 18. The method of claim 12, wherein the derivatives ofsulfonic acid are propanesulfonic acid, 2-methyl-1-propanesulfonic acid,benzenesulfonic acid, 3-methoxy-2-hydroxypropane sulfonic acid, ormixtures thereof.
 19. The method of claim 1, wherein the mass ratiobetween the acrylate moiety and the biobeneficial moiety is betweenabout 99:1 and about 1:1.
 20. The method of claim 1, wherein the massratio between the acrylate moiety and the biobeneficial moiety isbetween about 19:1 and about 9:1
 21. The method of claim 1, wherein themass ratio between the acrylate moiety and the biobeneficial moiety isabout 3:1.
 22. The method of claim 1, wherein the copolymer composingthe biobeneficial component has the formula:

wherein (a) m₁, n₁, p₁, r₁, m₂, n₂, p₂, and r₂ are all integers; (b)m₁≧0, n₁>0, p₁≧0, r₁>0; m₂≧0, n₂>0, p₂≧0, r₂>0; and (c) (i) if m₁=0,then p₁>0; (ii) if p₁=0, then m₁>0; and (iii) if m₂=0, then p₂>0; and(iv) if p₂=0, then m₂>0; and (v) r₁ and r₂ are the same or different;(vi) m₁ and m₂ are the same or different; (vii) n₁ and n₂ are the sameor different; and (viii) p₁ and p₂ are the same or different; (d) X ishydrogen or methyl group; (e) each of R, R₁, and R₂, independently, ismethyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, lauryl, or 2-hydroxyethyl; and (f) Q is a fragment providingthe copolymer with biobeneficial properties.
 23. The method of claim 1,wherein the copolymer composing the biobeneficial component ispoly(ethyleneglycol)-block-poly(n-butylmethacrylate)-block-poly(ethylene glycol),poly(n-butylmethacrylate)-block-poly(ethyleneglycol)-block-poly(n-butylmethacrylate), or mixtures thereof.